This proposal describes a 5-year training program for the development of an academic career in pulmonary medicine and immunology. The principle investigator has completed a residency program in Internal Medicine at Massachusetts General Hospital and is in the final year of a fellowship program in Pulmonary and Critical Care Medicine at Boston University School of Medicine. He now seeks to expand upon his scientific skills through an integration of intellectual, educational, and technical resources. This program will promote expertise in the area of T lymphocyte activation and proliferation as applied to pulmonary immune diseases. David Center will mentor the principle investigator's scientific development. Dr. Center is a recognized leader in the field of T cell biology. He is the Chief of Pulmonary and Critical Care Medicine and has trained numerous post-doctoral fellows and graduate students. In addition, an advisory committee of highly regarded medical scientists will provide scientific and career advice. Research will focus on regulation of T cell activation and proliferation by prointerleukin-16 (pro-lL-16). Pro- IL-16 is an abundant T cell nuclear and cytoplasmic protein. Our laboratory has demonstrated that pro-lL-16 is a potent suppressor of T cell growth, whose major affect is to arrest the cell cycle in G0/G1. This is associated with marked rises in the cell cycle inhibitor p27KIP1 following decreases in the ubiquitin ligase F box protein Skp2 which is associated with p27KIP1 degradation. Along these lines, following T cell receptor (TcR) activation, pro-lL-16 mRNA is markedly downregulated and pro-lL-16 protein disappears from the nucleus prior to cell cycle progression. Our hypothesis is that loss of nuclear pro-lL-16 is essential for cell cycle progression. We will test this hypothesis by: 1) Identifying pro-lL-16-regulated genes by microarray analyses that affect TcR-dependent activation and growth and 2) Determining the functional significance of pro-lL-16 regulation of selected cell cycle related genes. The Pulmonary Center of Boston University School of Medicine provides an ideal setting for training physician-scientists by incorporating expertise from diverse resources into programs individualized to meet the investigator's interests and skills. Such an environment maximizes the potential for the principle investigator to establish a scientific niche from which an academic career can be constructed.